2. Academic Validation
  3. MRNIP condensates promote DNA double-strand break sensing and end resection

MRNIP condensates promote DNA double-strand break sensing and end resection

  • Nat Commun. 2022 May 12;13(1):2638. doi: 10.1038/s41467-022-30303-w.
Yun-Long Wang  # 1 2,  Wan-Wen Zhao  # 1,  Shao-Mei Bai 1,  Li-Li Feng 1,  Shu-Ying Bie 1,  Li Gong 3,  Fang Wang 1,  Ming-Biao Wei 1,  Wei-Xing Feng 1,  Xiao-Lin Pang 2,  Cao-Litao Qin 1,  Xin-Ke Yin 1,  Ying-Nai Wang 4,  Weihua Zhou 5,  Daniel R Wahl 5 6,  Quentin Liu 7 8,  Ming Chen 9,  Mien-Chie Hung 10 11 12,  Xiang-Bo Wan 13 14
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China.
  • 2 Department of Radiation Oncology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China.
  • 3 Instrumental Analysis Research Center, Sun Yat-sen University, Guangzhou, Guangdong, 510275, PR China.
  • 4 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 5 Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
  • 6 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
  • 7 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, 116044, PR China.
  • 8 State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, PR China.
  • 9 State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, PR China. chenming@sysucc.org.cn.
  • 10 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. mhung@cmu.edu.tw.
  • 11 Graduate Institute of Biomedical Sciences and Research Centers for Cancer Biology and Molecular Medicine, China Medical University, Taichung, 404, Taiwan. mhung@cmu.edu.tw.
  • 12 Department of Biotechnology, Asia University, Taichung, 413, Taiwan. mhung@cmu.edu.tw.
  • 13 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China. wanxbo@mail.sysu.edu.cn.
  • 14 Department of Radiation Oncology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, PR China. wanxbo@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 35551189 DOI: 10.1038/s41467-022-30303-w
Abstract

The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection.

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